Down syndrome (DS), caused by triplication of chromosome 21, is the most frequent genetic cause of intellectual disability, with a prevalence of about one in 650-1000 live births worldwide [Bittles A H et al., Eur J Public Health (2007) 17(2):221-225]. Even though the etiology of the cognitive deficit in DS remains uncertain, cellular and anatomical abnormalities in the prenatal and perinatal forebrain and cerebellum suggest that early brain development is altered in individuals with DS. Similar central nervous system (CNS) abnormalities have been described in mouse models of DS. In particular, the Ts65Dn mouse, the most widely used model of DS, has abnormal forebrain and cerebellar development, defects in synapse formation and neurophysiology, and behavioral deficits.
Recent studies have suggested that the major functional defect in the postnatal Ts65Dn brain may be an imbalance between excitation and inhibition, e.g. a decreased numbers of excitatory synapses and a relative increase in inhibitory synaptic markers in the cortex and hippocampus. Further studies suggest that increased inhibitory synaptic drive may be a general physiological phenotype in the Ts65Dn forebrain.
There is currently no therapeutic option available for the treatment of cognitive deficit in people with DS. It has now been found, that inhibition of GABA A receptor function represents an attractive mechanism to treat cognitive impairment in DS.
The GABA A receptor regulating a chloride channel is the predominant inhibitory neurotransmitter receptor in the mammalian central nervous system and has been widely used as a target for neuromodulatory drugs. Many compounds in clinical use such as anxiolytics, sedatives, hypnotics or anti-epileptics increase GABA A receptor activation via the allosteric benzodiazepine (BZD) binding site. Such compounds have been termed “BZD site receptor agonists.” BZD binding site ligands producing the opposite effect, i.e., decreasing receptor activation, are called “BZD site receptor inverse agonists.” “BZD site receptor antagonists” are ligands which bind to the receptor without modulating its function but which block the activity of both agonists and inverse agonists [Haefely W E, Eur Arch Psychiatry Neurol Sci (1989) 238:294-301]. BZD receptor inverse agonists have so far only been tested in animal behavior experiments and in a very few exploratory human studies. The results showed beneficial activity, however, further development of the compounds that entered the clinic was prevented by anxiogenic effects, possibly resulting from the lack of selectivity shown by these agents for specific BZD receptor subtypes.
Non-selective antagonists, also called channel blockers, of the GABA A receptors (e.g. picrotoxin or PTZ) increase the risk of convulsions most likely through their actions on GABA A α1, α2, and α3 subunit containing receptors and, therefore, cannot be safely used in people with DS. It is hence a prerequisite that suitable GABA A receptor inhibitors are selective for the receptor subtype mainly involved in memory formation.
GABA A receptors are pentamers mostly consisting of two α, two β and a γ subunit. Several gene products are available for each of the subunits giving rise to a large number of receptor variants. The importance of different α subunit subtypes has been elucidated by the generation of transgenic mice lacking the normal diazepam sensitivity of the α1, α2, α3 or α5 subunit (α4 and α6 are diazepam insensitive). The results suggest that α1 is responsible for the sedative effects and α2 and perhaps α3 for the anxiolytic effects of BZD receptor ligand agonists [Löw K et al., Science (2000) 290(5489):131-134; Möhler H, Cell Tissue Res (2006) 326(2):505-516]. The consequences of a modified pharmacology of the α5 subunit are less evident, but reduced or no expression of the subunit could be associated with facilitated cognition in hippocampal-dependent tasks and importantly, no effects on anxiety or proconvulsant paradigms. This is in line with the preferential localization of α5 subunits in the hippocampus.